INTRODUCTION: Longitudinally extensive spinal cord lesions (LESCL) are characterized by T2-hyperintense signals spanning at least three vertebral body segments, with neuromyelitis optica spectrum disorders (NMOSD) being a significant cause. This study aimed to characterize the clinical, radiological, serological, and cerebrospinal fluid (CSF) features of LESCL and to compare NMOSD and non-NMOSD cases. METHODS: We conducted a retrospective cross-sectional study of adult patients diagnosed with LESCL at our center over a twelve-year period collecting data on demographics, clinical presentations, MRI findings, CSF analysis, and serological testing for AQP4-IgG and MOG-IgG antibodies. Etiologies were reviewed based on current diagnostic criteria, with comparisons made between NMOSD and non-NMOSD LESCL. RESULTS: We identified 41 LESCL cases, with NMOSD as the most common etiology (29.3 %) followed by ischemia (14.6 %) and multiple sclerosis (9.8 %). The median length of lesions was seven vertebral segments. Pleocytosis was present in 48.6 % of CSF analyses, with oligoclonal bands found in 10 cases. AQP4-IgG antibodies were positive in 11 of 12 NMOSD patients. NMOSD patients were more likely to be female (p = p.006), and exhibit severe symptoms, such as quadriparesis (p = 0.03) and a cervical sensory level (p = 0.04). MRI findings showed a preference for cervical lesions in NMOSD (p = 0.001) and thoracic lesions in non-NMOSD LESCL (p = 0.007). CONCLUSIONS: LESCL exhibit considerable clinical diversity, with NMOSD being the predominant etiology. Characteristics such as female sex and cervical MRI involvement may indicate a higher likelihood of NMOSD, while cases in males with thoracic segment involvement may suggest non-NMSOD etiologies such as ischemia.